tbuckley/cabot-search huggingface dataset:
The clinical relevance of humoral immune responses to Globo H-KLH vaccine adagloxad simolenin (OBI-822)/OBI-821 and expression of Globo H in metastatic breast cancer
Authors: Jung-Tung Hung, I-Ju Chen, Shir-Hwa Ueng, Chiun-Sheng Huang, Shin-Cheh Chen, Mu-Yi Chen, Yung-Chang Lin, Chun-Yen Lin, Michael J Campbell, Hope S Rugo, Alice L Yu
Journal: Journal for ImmunoTherapy of Cancer (2022)

An international randomized phase II trial of Globo H (GH) vaccine, adagloxad simolenin/OBI-821 in 349 patients with metastatic breast cancer showed longer progression-free survival (PFS) in vaccinated patients who developed anti-Globo H (anti-GH) IgG than those who did not and the placebo group. The impacts of anti-GH IgM and GH expression on peak anti-GH IgG and clinical outcome were further evaluated. The titers of anti-GH IgG and IgM were determined by ELISA. GH expression in tumor was examined by immunohistochemical staining. Immunophenotyping was conducted by flow cytometry. Adagloxad simolenin elicited anti-GH IgM which peaked at titers ≥1:80 between weeks 5 and 13. The mean anti-GH IgG titer peaked at week 41 and decreased thereafter on the completion of vaccination. One log increase in peak IgM was associated with 10.6% decrease in the HR of disease progression (HR: 0.894, 95% CI: 0.833 to 0.960, p=0.0019). Patients with anti-GH IgM ≥1:320 within first 4 weeks after vaccination had significantly higher maximum anti-GH IgM (p&lt;0.0001) and IgG titers (p&lt;0.0001) than those with &lt;1:320. Moreover, the median PFS appears to be longer for patients with anti-GH IgM ≥1:320 within first 4 weeks than those with anti-GH IgM titer &lt;1:320 (11.1 vs 7.3 months, p=0.164), but not statistically significant. Among patients with H score ≥80 for GH expression by immunohistochemistry, the vaccination group (n=42) seemed to have better PFS than the placebo group (n=23) (HR=0.59; 95% CI: 0.32 to 1.10, p=0.10), but the difference did not reach statistical significance. In addition, peak levels of anti-GH IgM were higher in patients who had lower percentage of activated regulatory T cells (Treg cells; CD4 + CD45RA - Foxp3 high ) at baseline than those who had higher activated Treg cells (p=0.042). This study demonstrates that adagloxad simolenin induced both IgG and IgM antibodies against GH. Anti-GH IgM ≥1:320 within first 4 weeks or low activated Treg cells at baseline may help to select patients who are likely to produce a higher level of GH-specific IgM and IgG in the future.
PB1929: PRELIMINARY STUDY OF EVALUATION IRON OVERLOAD MYOCARDIAL INJURY BY LOAD CT MYOCARDIAL PERFUSION IMAGING
Authors: Y. Zhang, W. Zhu, L.-X. Song, H. Long, C. Guo, C. Xiao, Z. Zhang, Y. Zhao, J. Su, J. Zhao, C. Chang
Journal: HemaSphere (2022)

Background: Currently, Iron overload cardiomyopathy(IOC) is assumed to be the most common cause of mortality in patients with secondary iron overload and is a major comorbidity in patients with genetic hemochromatosis. At present, there is still a lack of sensitive means to detect the injury of iron overload myocardium. Although ECG, echocardiography and serum ferritin level are simple and cheap methods to detect iron overload cardiomyopathy, they have no specificity for cardiac overload and are not sensitive to the injury caused by iron overload. Although echocardiography can determine the effect of iron on myocardial structure and function, but in patients with hemoglobinopathy and other hematological diseases, left ventricular diastolic dysfunction and decreased LVEF may be masked by the high output state caused by anemia. Recent literature showed CT myocardial perfusion imaging can well evaluate the effect of myocardial amyloidosis on myocardial function. Is it feasible to evaluate iron overload myocardial injury by CT myocardial perfusion imaging? There are few reports in the literature.Is the degree of cardiac iron overload consistent with the degree of myocardial injury? These problems need further study. Aims: This study investigated the relationship between iron overload(IO) myocardial injury and myocardial iron content Methods: Quantitative detection of cardiac virtual iron concentration (CVIC) and liver virtual iron concentration (LVIC)by energy spectrum CT.The myocardial blood flow (MBF) and myocardial extracellular volume fraction(ECV) was evaluated simultaneously by adenosine triphosphate (ATP) load CT myocardial perfusion imaging(CTPI), adjusted SF(ASF) were simultaneous detection.To analyze the correlation between myocardial injury and myocardial iron content. Results: ASF and LVIC is inconsistent with CVIC, patients with high ASF or LVIC but CVIC < 1.8 mg/ml had no myocardial injury. The myocardial injury appear in CVIC≥1.8 mg/ml patients but CVIC≥1.8 mg/ml patients were not all have myocardial injury. Transfusion dependence and iron chelation therapy (ICT) may be the influencing factors of iron overload myocardial injury. Image:Summary/Conclusion: IO myocardial injury appear in moderate and severe cardiac iron deposition patient,but the degree of myocardial injury was not inconsistent with myocardial iron content, so independent load CTPI testing is required. Relevant influencing factors need to be further studied.
PB2042: CLINICAL AND MOLECULAR CORRELATION OF PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA: A RETROSPECTIVE ANALYSIS FROM A TERTIARY CARE CENTER IN INDIA.
Authors: R. Balasubramanian, V. Arya, J. Kotwal, D. Gupta, N. Gupta
Journal: HemaSphere (2022)

Background: Approximately 50–70% of patients of ET harbor JAK2 mutation while about 20–30% patients carry CALR mutations. Data from developed countries has shown that CALR mutated patients have higher platelet count and lower thrombotic risk compared to JAK2 mutated patients. In India, testing for CALR and MPL mutation and next generation sequencing has become available only in last 5 years. There is lack of data regarding mutation status and its clinical correlation. We studied clinical features of ET patients presented to our hospital according to their mutation status. Aims: To study the molecular mutations and correlate them with the clinical features in ET patients Methods: We did the retrospective analysis of the patients diagnosed as ET from January 2016 to December 2021. Allele Specific PCR and fragment analysis was done to detect JAK2 (V617F), MPL (W515L/K) and CALR exon-9 mutations. Risk stratification done as per revised IPSET (International Prognostic Scoring for thrombosis in Essential Thrombocythemia) score. Therapy was started in all the patients according to their risk score with hydroxyurea or aspirin as the standard of care. Results: A total of 39 diagnosed cases of ET were identified. Median age was 55 years (30-83), 20/39 males (51.3%) and 19/39 females (48.7%). JAK2 mutation was found in 25.6% (10/39), CALR in 38.5% (15/39) and MPL in 5.1% (2/39) cases. Triple negativity was found in 30.8% (12/39) cases. Very low, low, intermediate and high-risk patients as per IPSET score were 53.9% (21/39), 10.2% (4/39), 20.5% (8/39) and 15.4% (6/39) respectively. The median age was statistically significantly lower in CALR positive cases compared to the JAK2 positive cases (45.9 vs 60.9years, p=0.011). The median Hemoglobin and platelet counts were slightly higher in CALR positive group (12.3 g/dL and 10.15x109/l) compared to JAK2 mutated and triple negative groups but the difference was not statistically significant. Three patients (7.7%) presented with thrombosis; two with cerebral venous thrombosis both CALR positive, one with arterial stroke and MPL gene mutation. Ten (25.6%) patients were lost to follow up. One (2.6%) died to pulmonary infection. Median follow up period was 24 months. None of the patient transformed to acute myeloid leukemia or myelofibrosis. None of the patient developed thrombotic event after diagnosis and appropriate treatment. Summary/Conclusion: We observed that CALR was the most common mutation in our study. The CALR mutated patients were younger in age but the median platelet counts, WBC count and Hemoglobin were not statistically different among different mutation groups. In contrast to western studies, thrombosis was observed to be higher in CALR mutated group than others in our patient population. We recommend larger multicenter study for further elucidation of these observations.
PB2050: EVALUATION OF NON-CLONAL ERYTHROCYTOSIS: SINGLE CENTRE EXPERIENCE
Authors: A. Šumah, N. Vodošek Hojs, M. Dreisinger
Journal: HemaSphere (2022)

Background: Secondary erythrocytosis has a broad differential diagnosis that includes hypoxic lung disease, cyanotic congenital heart disease, kidney disease, medications and erythropoietin-producing malignant disorders. Aetiology remains unknown in some patients, they have the so-called idiopathic erythrocytosis (IE). Among the latter, patients with inherited/congenital erythrocytosis can be found, especially if they have a positive family history. Aims: The aim of our study was to analyse the characteristics of non-clonal erythrocytosis in patients referred to our Haematology department in a 5-year period (2016 – 2021) and to compare the IE group to the group with known causes. Methods: We included all individuals who were Janus kinase 2 (JAK2) mutation negative and had erythrocytosis. Data was retrospectively collected with the help of the hospital database and statistically analysed with SPSS. Results: The study included 250 patients, 176 (70%) men and 74 (30%) women, with mean age 58.8 years (21 – 94 years). Their average haemoglobin values within a 1-year time period were 182.5 g/L for men and 169 g/L for women. Average haematocrit levels were 0.53 for men and 0.50 for women. Elevated erythropoietin (EPO) levels were found in 10.5% patients, 83.4% had normal and 6.1% decreased values. Symptoms were reported by 48% of the patients, mostly itchiness (16.4%), sweating (12%) and other (30%) such as tinnitus, myalgia, joint pain and snoring. The most probable reasons for secondary erythrocytosis were smoking/chronic obstructive pulmonary disease (COPD) (32%), IE (29%), dehydration (7%), nephrological aetiology (6%), obesity (4%), sleep apnoea (4%), asthma (4%), infection (4%), heart or pulmonary disease hypoxia (4%), possible hemochromatosis (3%), medications (2%) and high altitude/training (1%). Patients with IE had an average age of 57.2 years (24 – 83 years), 57 (78%) were men and 8 (11%) had a positive family history. EPO levels in this group were elevated in 7.8%, normal in 88.2% and decreased in 3.9%. Past thrombotic events were reported by 23.3% of individuals with IE and 20.3% of patients with known secondary cause. There was no statistical difference in age, gender, EPO, haemoglobin levels and past thrombotic events between the IE group and group with known causes. Patients with IE significantly differed from the group with known causes in haematocrit levels (p=0.0219) with lower levels in IE patients. Summary/Conclusion: Among 250 patients with non-clonal erythrocytosis the majority had acquired aetiology. The most common cause was hypoxia caused by smoking or COPD. Patients with IE significantly differed from the group with known causes in haematocrit levels, while there were no significant differences between groups in age, gender, EPO levels, haemoglobin levels and past thrombotic events.
PB2205: ANTI-INFLAMMATORY AND REGENERATIVE EFFECTS OF UMBILICAL CORD BLOOD ENDOTHELIAL PROGENITOR CELL-DERIVED EXTRACELLULAR VESICLES ON ENDOTHELIAL CELLS IN VITRO
Authors: S. Ben Fraj, A. Aouida, G. Uzan, H. Houda
Journal: HemaSphere (2022)

Background: Circulating endothelial progenitor cells (EPCs) play a pivotal role in vascular regeneration and the repair of diseases in which angiogenesis is required including ischemia and tissue transplantation. Although a potentially valuable cell therapy tool their clinical use remains limited due to suboptimal storage conditions and especially, immune rejection. EPC-derived extracellular vesicles (EPC-EVs) may be an attractive alternative given their role in cell-cell communication and expression of the same parental markers. Aims: In this study, we investigated the regenerative effects of umbilical cord blood EPC-EVs on endothelial cells in vitro Methods: EPCs were obtained from human umbilical cord blood (UCB) and characterized by flow cytometry. Briefly, mononuclear cells were isolated by Ficoll and seeded on collagen-coated plates. After 7-20 days, colony-forming cells were amplified and cultured in a medium containing an EVs-depleted serum. Then the conditioned medium (1L) was used to isolate the EVS with Tangential Flow Filtration (MWCO 500KDa). The EVs were characterized by Nanoparticle Tracking Analysis (NTA) and Western blot. The angiogenic effects of EPC-EVs on endothelial cells were investigated with transwell migration, wound healing and tube formation assays. We also analyzed the expression of pro and anti-inflammatory markers and NO production by flow cytometry. In all the experiments, several EV doses were assessed. Results: Our study shows that purified EPC-EVs (179,6 nm diam) enhance the migration and tube formation of endothelial cells. Moreover, they have an anti-inflammatory effect and do not change the NO level. Summary/Conclusion: Our isolated EPC-EVs have the same beneficial properties (proangiogenic, anti-inflammatory) than their parent cells. In the next step, we shall confirm these results in vivo.
PB2196: EQUATOR: A PIVOTAL PHASE 3 DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY OF ITOLIZUMAB IN COMBINATION WITH CORTICOSTEROIDS FOR THE INITIAL TREATMENT OF ACUTE GRAFT-VERSUS-HOST DISEASE
Authors: J. Koreth, L. Kean, L. Chinn, L. M. Acevedo, O. Bandman, J. Rothman, S. Connelly, D. Thomas, C. Cutler
Journal: HemaSphere (2022)

Background: Acute graft-versus-host disease (aGVHD) remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplant (allo-HSCT); however, there is still no approved first-line treatment and corticosteroids (CS) remain standard of care. Itolizumab is a humanized IgG1 monoclonal antibody that binds CD6 and blocks interaction with activated leukocyte cell adhesion molecule (ALCAM) to inhibit T effector cell activity and trafficking to target organs. This mechanism of action represents a promising therapeutic approach to treat aGVHD, as suggested by safety and efficacy results from EQUATE (NCT03763318), an open-label Phase 1b/2 study that evaluated itolizumab in combination with CS as treatment for newly diagnosed aGVHD. The benefit-risk profile currently observed in EQUATE for doses of 0.8 and 1.6 mg/kg supports continued evaluation of itolizumab in a pivotal Phase 3 study. Aims: EQUATOR is a pivotal Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of itolizumab in combination with CS as initial treatment for subjects with aGVHD. This global study will enroll approximately 200 subjects ≥12 years old who are diagnosed with Grade III-IV or Grade II with lower gastrointestinal involvement aGVHD following initial allo-HSCT. Methods: To be eligible, subjects must start study treatment within 72 hours of starting CS treatment for aGVHD (Day 1 CS dose must be 2 mg/kg/day). Eligible subjects will be randomized 1:1 to receive 7 IV doses of itolizumab (1.6 mg/kg on Day 1 and 0.8 mg/kg for the subsequent 6 doses) or placebo every two weeks. Subjects will be followed for one year (Figure). The selected dosing regimen is expected to rapidly decrease CD6 from the surface of T cells and maintain low surface CD6 throughout the dosing interval. An interim analysis for futility and efficacy will be conducted when approximately 50% of subjects complete through Day 29. Results: The primary endpoint is the complete response (CR) rate at Day 29 and key secondary endpoints include Day 29 overall response rate and durable CR rate at Day 99. This will enable assessment of speed and sustainability of symptom improvement and resolution. Additional secondary efficacy endpoints include the evaluation of duration of response, survival outcomes, CS use, and chronic GVHD incidence. Safety endpoints include the incidence of treatment-emergent adverse events (AEs), serious AEs, infections and CMV and EBV reactivation. Image:Summary/Conclusion: Here we present the rationale and design of EQUATOR, a pivotal Phase 3 study that will evaluate itolizumab in combination with CS and the ability to induce rapid and durable CR rates for the initial treatment of aGVHD.
Cancer-Associated Fibroblasts Suppress CD8+ T-cell Infiltration and Confer Resistance to Immune-Checkpoint Blockade
Authors: Liam Jenkins, Ute Jungwirth, Alexandra Avgustinova, Marjan Iravani, Adam Mills, Syed Haider, James Harper, Clare M. Isacke
Journal: Cancer Research (2022)

Abstract Immune-checkpoint blockade (ICB) promotes antitumor immune responses and can result in durable patient benefit. However, response rates in breast cancer patients remain modest, stimulating efforts to discover novel treatment options. Cancer-associated fibroblasts (CAF) represent a major component of the breast tumor microenvironment and have known immunosuppressive functions in addition to their well-established roles in directly promoting tumor growth and metastasis. Here we utilized paired syngeneic mouse mammary carcinoma models to show that CAF abundance is associated with insensitivity to combination αCTLA4 and αPD-L1 ICB. CAF-rich tumors exhibited an immunologically cold tumor microenvironment, with transcriptomic, flow cytometric, and quantitative histopathologic analyses demonstrating a relationship between CAF density and a CD8+ T-cell–excluded tumor phenotype. The CAF receptor Endo180 (Mrc2) is predominantly expressed on myofibroblastic CAFs, and its genetic deletion depleted a subset of αSMA-expressing CAFs and impaired tumor progression in vivo. The addition of wild-type, but not Endo180-deficient, CAFs in coimplantation studies restricted CD8+ T-cell intratumoral infiltration, and tumors in Endo180 knockout mice exhibited increased CD8+ T-cell infiltration and enhanced sensitivity to ICB compared with tumors in wild-type mice. Clinically, in a trial of melanoma patients, high MRC2 mRNA levels in tumors were associated with a poor response to αPD-1 therapy, highlighting the potential benefits of therapeutically targeting a specific CAF subpopulation in breast and other CAF-rich cancers to improve clinical responses to immunotherapy. Significance: Paired syngeneic models help unravel the interplay between CAF and tumor immune evasion, highlighting the benefits of targeting fibroblast subpopulations to improve clinical responses to immunotherapy.
PB2026: CONSENSUS STATEMENT: IMPORTANCE OF TIMELY ACCESS TO MULTIPLE MYELOMA DIAGNOSIS AND TREATMENT IN CENTRAL AMERICA AND THE CARIBBEAN
Authors: M. Pimentel, O. D. F. Espinal Jaquez, F. Godinez, F. Jimenez, D. Martinez, N. Mendoza, A. Quintana, J. Richmond, E. Romero
Journal: HemaSphere (2022)

Background: Background: In Central America and the Caribbean, multiple myeloma (MM) patients face significant barriers to diagnosis and treatment. Aims: Aims: To describe the current situation of MM in the region, discuss the current barriers to timely diagnosis and proper treatment, and develop consensus recommendations to address these issues. Methods: Methods: Nine experts from five countries took part in a virtual consensus meeting on MM in Central America and the Caribbean. During the meeting, experts analyzed the disease burden, the current conditions for disease management, and access to treatment in the region. The participants reached a consensus on the extent of the problem and the necessary measures. Results: Results: Hard evidence on the incidence and prevalence of MM in the region is scarce, but the experts perceive an increase in MM cases. The lack of data on the direct and indirect costs at the local and regional levels obscures the impact of the disease and limits awareness among decision-makers. Most patients are diagnosed late, and face long waiting times and geographical barriers to access treatment. Access to efficacious innovative therapies that increase survival time is limited due to access barriers within health systems. Image:Summary/Conclusion: Conclusion: There was consensus on five recommendations: 1) to generate evidence; 2) to educate the public; 3) to increase timely diagnosis and facilitate access to treatment; 4) to promote interaction, collaboration, and participation among all sectors involved in the decision-making process; and 5) to guarantee timely access to new therapies.
P1586: IN-HOSPITAL MORTALITY AND POOR PROGNOSIS FACTORS ASSESSMENT IN PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA AND COVID-19.
Authors: D. Ivanova, E. Baryakh, T. Tolstykh, T. Chudnova, Y. Polyakov, O. Kochneva, M. Litvinenko, E. Misyurina, K. Yatskov
Journal: HemaSphere (2022)

Background: Acute lymphoblastic leukemia (ALL) belongs to a heterogeneous, highly aggressive group of hematologic malignancies. In the context of the epidemic of a new coronavirus infection (COVID-19), patients with hemoblastoses have a more severe course of the viral infection and high mortality rate due to COVID-19. The management protocols of patients with ALL in the context of the COVID-19 pandemic has not been developed, and approaches to both the treatment of a new coronavirus infection and the antitumor treatment of ALL in patients with COVID-19 have not been defined. Aims: To analyze in-hospital overall survival of patients with acute lymphoblastic leukemia and coronavirus infection, to assess the impact of poor prognostic factors on the outcome of the disease, and to determine the therapeutic tactics for ALL and COVID-19. Methods: From April 21, 2020 to November 30, 2021 46 patients with ALL (24 men, 22 women) with a median age of 44.5 (18-74) years were observed on the basis of the hematological service of the City Clinical Hospital No. 52 (Moscow). According to the immunophenotypic variant of ALL, 27 (59%) were patients with B-ALL, of which Ph-positive ALL was diagnosed in 8 (30%), Ph-negative - in 19 (70%); T-ALL - 16 (35%), biphenotypic - 2 (4%). Patients with newly diagnosed ALL (20%) underwent induction antitumor therapy, 67% - convalescents and PCR positive for SARS-CoV-2 infection. To determine the factors of hospital mortality, a statistical analysis was performed, including: age, hematological disease status, degree of lung tissue damage according to computer tomography (CT), stay in the intensive care unit due to severe respiratory failure requiring mechanical ventilation (ALV), the presence of neutropenia of the IV degree, transfer from another hospital, the formation of an antiviral immune response after a coronavirus infection. Results: Hospital mortality in ALL patients was 30%. Statistically significant factors for poor prognosis were: age (>40 years), p=0.033, hematological disease status (newly diagnosed ALL, progression/relapse), p=0.004, high (≥50%) degree of lung tissue damage according to CT (p =0.003), neutropenia IV degree (p=0.004), their transfer to another hospital, stay in the intensive care unit and mechanical ventilation (p=0.004). Summary/Conclusion: The main adverse factors affecting hospital mortality were the absence of ALL remission and the presence of severe infectious complications. Carrying out antitumor therapy allows to stabilize the status of ALL and is an important aspect in the simultaneous course of coronavirus infection. In patients with ALL and confirmed coronavirus infection, the decision to conduct induction therapy should be discussed on an individual basis, depending on ALL status, the activity of coronavirus infection and comorbidity status.